A study on the regio- and stereoselectivity in palladium-catalyzed cyclizations of alkenes and alkynes bearing bromoaryl and nucleophilic groups

Article abstract of DOI:10.1016/j.tet.2004.03.023

We have studied the remarkable dependence of the stereochemistry of the cyclization on the double bond geometry and of the effect of the bulkiness of the nucleophile on the regiochemistry of the palladium mediated cyclization of alkenes bearing aryl bromides and nucleophiles. In contrast, the cyclization of the acetylenic homologous substrates is not dependent on the nature of the nucleophile.

Full text of DOI:10.1016/j.tet.2004.03.023

Tetrahedron 60 (2004) 4007–4017
A study on the regio- and stereoselectivity in
palladium-catalyzed cyclizations of alkenes and alkynes bearing
bromoaryl and nucleophilic groups
*
` `
Didier Bruyere, Didier Bouyssi and Genevieve Balme
´
Laboratoire de Chimie Organique 1, CNRS UMR 5181, Universite Claude Bernard, Lyon I, CPE, 43 Bd du 11 Novembre 1918,
´
69622 Villeurbanne Cedex, France
Received 6 October 2003; revised 30 January 2004; accepted 5 March 2004
Abstract—We have studied the remarkable dependence of the stereochemistry of the cyclization on the double bond geometry and of the
effect of the bulkiness of the nucleophile on the regiochemistry of the palladium mediated cyclization of alkenes bearing aryl bromides and
nucleophiles. In contrast, the cyclization of the acetylenic homologous substrates is not dependent on the nature of the nucleophile.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Control of regio- and stereochemistry during the simul-
taneous creation of consecutive stereogenic centers continue
to offer considerable challenge to organic chemists.1
Transition metal-mediated tandem or cascade reactions
have recently emerged as new and powerful methods, which
are aimed at achieving this goal. The scope and limitations
of such reactions have been the subject of recent reviews.2
Following this trend, we have developed a new palladium-
mediated cyclization reaction of unsaturated substrates
Scheme 1.
bearing a nucleophilic substituent.3 By using the intra-
molecular version of this strategy, we have already achieved
the stereocontrolled synthesis of fused tricyclopentanoid4
that, due to the stereochemistry of the initial double bond
substrate, the ring fusion in compound 2 must be trans. The
relative configuration of 3 would be fixed for the same
and linearly condensed hexahydro-1H-benz[f]indenes.5 It is
noteworthy that these cyclizations proceed in a completely
reason. Moreover, examination of molecular models led us
trans-stereoselective manner since they involve attack of
the carbon nucleophile onto the double bond which is
electrophilically activated by the organopalladium species.
to believe that the bulkiness of the nucleophile would be a
determining factor controlling the selectivity (5-exo- versus
6-endo-trig) of the reaction. In general, exo-cyclization is
kinetically more favorable than the endo mode of attack. In
the particular case of a substrate of type 1, the geometric
requirement for the intramolecular palladium-mediated
It was envisioned that application of the same concept to
linear substrates having an internal trans double bond such
as E1 would either proceed via a 5-exo or a 6-endo-trig
cyclization in the 6-endo-trig process seems to induce less
process leading to tricyclic compounds 2 and 3, respectively
(Scheme 1). We thought that the syntheses of these two
tricyclic compounds would occur with concomitant stereo-
between a bulky nucleophile and one of the allylic
control of the two newly formed adjacent carbon centers
since the nucleophile and the organopalladium species add
in a trans fashion across the unsaturated linkage. This means
strain in the transition state relative to attack according to
5-exo-trig process. However, severe steric interactions
hydrogens of the linear substrate could be anticipated in
the endo-cyclization mode. We were therefore interested to
see if these steric interactions could be used as stereo-
controlling elements during the cyclization. Indeed, a thin
nucleophile would favor 5-exo pathway, while the 6-endo-
trig would be preferred in the presence of a bulky
nucleophile (Scheme 1). We also wanted to examine the
Keywords: Stereoselectivity; Biscyclization; Palladium.
*
Corresponding author. Tel.: þ4-72-43-14-16; fax: þ4-72-43-12-14;
e-mail address: balme@univ-lyon1.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.023

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4008
importance of olefin geometry on the stereochemical course
of the cyclization.
Initial experiments to cyclize the trans alkene 1a using
previously developed methodology in our group failed.4
Therefore, when a solution of 1a in THF was treated with
1.1 equiv. of tBuOK, followed by addition of 5 mol% of
Pd(dppe),8 no reaction was observed and starting material
was recovered even after prolonged reflux times. Optimum
conditions of our tandem biscyclization reaction performed
on the substrate E1a involved formation of the enolate
with tBuOK, in presence of 5 mol% of Pd(dppe), in dry
1-methyl-2-pyrrolidinone (NMP) at 50 8C. After 24 h, the
starting material was consumed and a 1:1 mixture of two
tricyclic compounds was obtained in 70% combined yield.
In this paper, we report details of our work6 and show that
the cyclization proceeds with virtually complete regio- and
stereocontrol. Moreover, the reaction is shown to be
stereospecific with the stereochemical outcome depending
on the geometry of the internal alkene.
2. Results and discussion
1
The H NMR of the crude reaction product revealed no
traces of bicyclic products resulting from the competing
Heck reaction (Scheme 3).
2.1. Cyclization of linear trans-alkenes E1a–c
In order to validate the feasibility of our strategy, the
palladium catalyzed cyclization reactions of linear trans
alkenes of type E1a–c differing in the bulkiness of the
nucleophilic moiety were investigated. The cyclization
substrates E1a–c were prepared via the route outlined in
Scheme 2, in a seven-step sequence from commercially
available 1-bromo-2-iodobenzene. Thus treatment of this
dihalide with allylic alcohol, in DMF, at 50 8C, according to
the procedure published by Jeffery7 [Pd(OAc)2, benzyl-
triethylammonium chloride, NaHCO3] afforded the single
aldehyde 4 in 92% yield. Treatment of 4 with vinyl-
magnesium bromide led to allylic alcohol 5 in 90% yield.
The orthoester Claisen rearrangement of 5 proceeded in
triethylorthoacetate at reflux to give 80% of the ester 6.
Reduction of 6 with lithium aluminium hydride in diethyl
ether cleanly provided the alcohol 7 which was transformed
to the iodide 8 via the corresponding mesylate. Substitution
of the iodide group by the sodium salts of methyl
cyanoacetate, dimethyl malonate and malononitrile,
respectively, furnished the corresponding precursors
E1a–c.
Scheme 3. Reaction conditions: (a) Pd(OAc)2 5%, dppe 10%, 1-heptene
10%, 18-C-6 crown ether 20%, tBuOK, NMP, 50 8C.
These two tricyclic compounds were separated by careful
medium pressure liquid chromatography and their structures
1
were confirmed by H and 13C NMR data. The solid less
polar product was identified as one epimer of trans-2a by a
400 MHz two dimensional DQF COSY spectrum and a
1H–13C HMQC experiment (heteronuclear multiple
quantum coherence) recorded in the phase-sensitive mode
that permit identification of most of the hydrogens and
carbons.9 Thus, H4a resonates at d¼2.12 ppm as doublet of a
doublet of a doublet. The J4a–10a, J4a–4a ax and J4a–4a eq
constants were 12.1, 11.3, 3.9 Hz, respectively, and were
consistent with the expected two large coupling constants
Jax–ax and one Jax–eq of a trans-octahydrophenanthrene.10
The structure assigned to the liquid more polar product was
one epimer of anti-3a by arguments analogous to those
made for the assignment of trans-2a. In the 1H NMR,
the double doublet of doublets at 3.4 ppm is assigned to the
H10a angular proton. It is coupled to the adjacent H10
0
and H10 protons by coupling constants J10a–10¼8.3 Hz,
0
J10a–10 ¼7.1 Hz typical of a five-membered ring. The
splitting of the H10a signal is due to its coupling with the
adjacent angular proton H4a (J10a–4a¼11.5 Hz) and this
confirms the expected anti relationship between them.
As expected, the palladium induced cyclization of E1a
bearing a medium size nucleophile proceeded via both exo
and endo-pathway, but surprisingly, only one diastereomer
of trans-2a and anti-3a were formed at the carbon bearing
the nitrile and the ester. The configuration of the quaternary
center was not determined. Next, we attempted the
cyclization of substrate E1b bearing a bulky nucleophile.
This was carried out under the usual reaction conditions
used for E1a. After 5 h at 60 8C, the reaction provided
exclusively compound anti-3b which was isolated in 55%
yield after chromatographic purification. No traces of the
other regioisomer or of classical Heck reaction product were
Scheme 2. Reagents and conditions: (a) allyl alcohol, Pd(OAc)2 5%,
NaHCO3, TEBA, DMF, 50 8C; (b) vinylmagnesium bromide, THF, 230–
25 8C, 2 h; (c) CH3–C(OEt)3, propionic acid, reflux, 12 h; (d) LiAIH4,
ether, 25 8C, 30 min; (e) MsCl, TEA, CH2Cl2, 0 8C, 2 h;(f) Nal, acetone,
reflux, 12 h; ((g) NaH, dimethylmalonate, DMF/THF 1/1, reflux, 18 h;
(h) NaH, malononitrile, THF, reflux, 12 h; (i) NaH, methylcyanoacetate,
DMF/THF 1/1, reflux, 12 h.
1
observed within the limits of H NMR and capillary GC

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4009
sensitivities. The stereostructural assignments for the
tricyclic compound were verified by comparison of its
characteristic 1H NMR data with those of anti-3a. In
particular, the trans relationship between H10a and H4a was
readily deduced from the coupling constant J10a–4a¼11 Hz
(Scheme 4).
junction of the ring was confirmed by its 1H NMR spectrum
in C6D6 in which the H10a proton resonates at d¼1.50 ppm
and its coupling pattern as a doublet (J¼4.3 Hz) of triplet
(J¼12 Hz) consistent with a small Jax–eq and two large Jax–
couplings. In addition, a single crystal X-ray diffraction
ax
analysis confirmed the stereochemical assignment of this
diastereomer (Fig. 1).
This last result shows that, in this case, the tandem
carbopalladation–cyclization sequence proceeds with com-
plete regio- and stereoselectivity leading to the trans
perhydrophenanthrene ring. This system is very common
in natural products, particularly in the carbon framework of
steroids and many triterpenoids.12
2.2. Cyclization of linear cis-alkenes Z1a–c
Since the ring junction stereochemistry is governed by
alkene geometry, a question which is raised by these
successful preliminary results is the stereospecificity of this
tandem carbopalladation–cyclization sequence. In order to
gain further insight into this problem, we investigated the
cyclization of Z linear substrates of type 1 (Scheme 5).
Scheme 4. Reaction conditions: (a) Pd(OAc)2 5%, dppe 10%, 1-heptene
10%, 18-C-6 crown ether 20%, tBuOK, NMP, 50 8C.
This result clearly indicates that the 5-exo-cyclization can
be controlled by judicious choice of the nucleophile
substituent. Finally, we turned our attention to the cycliza-
tion of the substrate E1c bearing a thin nucleophile. In
contrast to the facile cyclization of substrates E1a and E1b,
E1c appeared to be more resistant since using the procedure
mentioned above, all the starting material was only
consumed after 65 h at 60 8C.11 A colorless solid was
isolated in 52% yield after flash-chromatography and
characterized as the regioisomer trans-2c, resulting from
the 6-endo-trig cyclization process on the basis of spectro-
scopic correlation with trans-2a (Scheme 4). The trans
Scheme 5.
Using molecular model, we speculated as previously
described for the cyclization of trans isomers, that the
regioselectivity would depend again upon steric factors.
Indeed, in the approach of the nucleophile to the internal
double bond, a strong interaction was observed between one
of the allylic hydrogens and the nucleophile. Bulky ones
would therefore favor the 5-exo cyclization while smaller
ones would shift the reaction to the expected 6-endo
pathway. The success of such a reaction would lead to the
synthesis of the cis-octahydrophenanthrene skeleton. It is
noteworthy that a few synthetic methodologies have been
developed to construct this core structure which is of current
interest.13
Access to the required starting material Z1a–c proved to
be straightforward with the key step being a Wittig
condensation of the known phosphonium salt14 with the
aldehyde 4 giving the Z-alkene 9 with complete stereo-
selectivity. Conversion of the chloride to the iodide 10
followed by reaction with the sodium salts of methyl
cyanoacetate, dimethyl malonate and malononitrile,
respectively, produced the corresponding precursors Z1a,
Z1b, Z1c (Scheme 6).
Treatment of Z1a with Pd(dppe) (5 mol%) and tBuOK
(1.1 equiv.) in NMP at 50 8C afforded an inseparable
Figure 1. X-ray crystallographic structure of compound trans-2c: ORTEP
view.

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4010
dimethylmalonate group again exerts a profound influence
upon the regiochemistry of cyclization process by virtue of
its steric bulk.
Finally, we have investigated the cyclization of Z1c bearing
a smaller nucleophile. This reaction was performed at 50 8C
for 48 h to afford the single crystalline cis octahydro-
1
phenanthrene 2c in 52% yield (Scheme 8). The small H
NMR coupling (J¼3.7 Hz) observed between the angular
hydrogens confirmed the expected cis ring fusion of 2c. The
13C NMR spectrum displays two methine carbons (36.8 and
40 ppm) showing that the carbons of the ring junction in cis-
2c are more shielded than those of trans-2c (38.8 and
44.5 ppm). This is in accordance with the fact that the 13C
NMR shift values for a cis ring junction of perhydro-
phenanthrenes are smaller than those for a trans junction.15
Single X-ray diffraction analysis unambiguously established
the expected stereochemistry as shown in Figure 2.
Scheme 6. Reagents and conditions: (a) (4-chlorobutyl)-triphenyl-
phosphonium bromide, KHMDS, THF, 0 8C; (b) Nal, acetone, reflux,
12 h; (c) NaH, methylcyanoacetate, DMF/THF 1/1, reflux, 12 h; (d) NAH,
dimethylmalonate, DMF/THF 1/1 reflux, 18 h; (e) NaH, malononitrile,
THF, reflux, 12 h.
mixture of four isomeric tricyclic compounds in a ratio of
about 4:4:1:1 after only 1.5 h (according to GC) and in 94%
yield. We suspected that these four substrates were two
couples of diastereomers for each of the regioisomers, cis-
2a and syn-3a. The 1H and 13C NMR spectra of the mixture
were significantly different from those reported for trans-2a
and anti-3a and no traces of compounds resulting from a
Heck reaction were observed. Because of the low regio- and
diastereoselectivity (referred to C1 carbon) exerted in this
cyclization, we decided not to investigate which of the four
isomers were predominant (Scheme 7).
The remarkable influence of the double bond geometry of
the starting material on the stereochemistry of the product
was here also demonstrated. Furthermore, the regio-
chemistry of the cyclization could be controlled by the
size of the nucleophile.
2.3. Cyclization of the acetylenic substrates 14a–b
It was of interest to examine the behavior of the
corresponding acetylenic substrates under our standard
conditions of cyclization. We wanted to know if the
bulkiness of the nucleophile could also exert a beneficial
directing effect on the regioselectivity during the palladium
mediated cyclization leading either to cyclopentylidenin-
dane 15 or to hexahydrophenanthrene 16 (Scheme 9).
Scheme 7. Reaction conditions: (a) Pd(OAc)2 5%, dppe 10%, 1-heptene
10%, 18-C-6 crown ether 20%, tBuOK, NMP, 50 8C.
To this end, syntheses of the two required acetylenic
substrates were each accomplished in a four step sequence
starting from the commercially available 2-bromobenzyl
bromide as illustrated in Scheme 10. The required Grignard
reagent was generated in situ in diethyl ether, from
propargyl bromide and magnesium turnings and then
added to 2-bromobenzyl bromide to provide 11 in 75%
yield. Deprotonation of the resulting acetylenic product by
lithium diisopropylamide (LDA) followed by addition of an
excess of 1-bromo-3-chloropropane afforded chloride 12 in
60% yield. Halide exchange (NaI, acetone) gave the desired
iodide 13 in excellent yield. This iodide was treated with the
sodium salts of dimethylmalonate and malonitrile to
respectively produce the corresponding acetylenic
precursors 14a and 14b.
Interestingly, treatment of Z1b under the same conditions
gave syn-3b as a single diastereomer in 90% yield after 12 h
at 50 8C (Scheme 8). Spectral data clearly indicated the
five-membered ring: in particular, the C10 axial proton at d
2–2.5 ppm has the expected coupling pattern (ddd, J¼7.1,
8.8, 13.8 Hz). The cis relationship between H4a and H10a
was established by the coupling constant (J¼3 Hz) in the
homonuclear decoupling spectrum (Scheme 8).
This result indicates that the pallado-catalyzed cyclization
of linear compounds 1b is stereospecific and that the
The cyclization of substrate 14a under the conditions
previously used for alkenyl compounds gave, after 24 h at
60 8C, an inseparable mixture of two products in a 3:2 ratio
1
1
(as determined by H NMR). In the H NMR spectrum of
the product mixture, the minor compound appeared to be 17
resulting from the competing Heck reaction with a proton
triplet centered at 3.38 ppm characteristic of proton at the a
position of a malonate function, and a vinylic proton at
4.6 ppm. For the major product, the absence of these two
protons strongly suggested the biscyclization had taken
place but the regiochemistry of the cyclization (6-endo
versus 5-exo) could not be ascertained. In order to improve
Scheme 8. Reaction conditions: (a) Pd(OAc)2 5%, dppe 10%, 1-heptene
10%, 18-C-6 crown ether 20%, tBuOK, NMP, 50 8C.

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4011
Figure 2. X-ray crystallographic structure of compound cis-2c: ORTEP view.
the selectivity in favor of the biscyclized product, we
decided to test the reaction in DMSO. In this solvent, the
reaction was complete after 2 h at 90 8C leading to the
previously obtained tricyclic compound (15a or 16a) in 58%
yield as the only isolable product. To determine the
structure of this unsaturated substrate, the alkene was
oxidatively cleaved by treatment with ozone16 followed by
addition of dimethylsulfide leading to two products. The
mixture was analyzed by GC–MS proving the presence of
1-indanone 18 by comparison with an authentic sample. The
second product shown an ion peak at Mþ¼200 according to
the structure of 19. This result clearly demonstrated the
cyclopentylindanylidene structure 15a and not 16a for the
biscyclization product (Scheme 11).
Scheme 9.
Same conditions were applied to 14b leading after 2 h to a
unique crystalline product in 48% yield. The regiochemistry
of this compound was derived from a single X-ray
diffraction analysis and revealed the cyclopentylindanyl-
idene structure 15b (Fig. 3). Contrary to the ethylenic
substrates, the regioselectivity of the biscyclization process
of the acetylenic homologs is independent of the bulkiness
of the nucleophile.
3. Conclusion
In summary, we have demonstrated that the simple tandem
palladium-catalyzed cyclization of linear compound of type
Z or E proceeds with complete retention of the stereo-
chemistry in a stereocontroled mode. Moreover, it was
possible to effect either 5-exo or 6-endo-cyclization
Scheme 10. Reagents and conditions: (a) propargyl bromide, Mg, HgCl2
cat., ether THF, 0 8C; (b) LDA, 278 8C, 1 h then 1-bromo-3-chioro-
propane, 260 8C to reflux, 12 h; (c) Nal, acetone, reflux, 12 h; (d) NaH,
dimethylmalonate, DMF/THF 1:1, reflux, 18 h; (e) NaH, malononitrile,
THF, reflux, 12 h.

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4012
Scheme 11. Reagents and conditions: (a) Pd(OAc)2 5%, dppe 10%, 1-heptene 10%, 18-C-6 crown ether 20%, tBuOK, DMSO, 90 8C, 2 h; (b) O3, CH2Cl2,
278 8C; (c) DMS, 278 8C to 25 8C.
reactions were monitored by thin layer chromatography
carried out on 0.2 mm silica gel plates (60 F-254, Merck) or
by gas chromatography on a DB 1 capillary column 30 m.
Column chromatographies were performed on a silica gel Si
60 (40–63 mesh, Merck). Melting points are uncorrected.
IR spectra were recorded on a Perkin–Elmer 337
instrument. Nuclear magnetic resonance spectra were
obtained on a Brucker AC 200 spectrometer (1H:
200 MHz or 13C: 50 MHz) or on a Brucker AC 300
spectrometer (1H: 300 MHz or 13C: 75 MHz) using TMS as
an internal standard. Chemical shifts were expressed in ppm
downfield from TMS and coupling constants (J) in Hertz.
Microanalysis were performed by Service Central
d’Analyse du CNRS, Solaize, France. THF was distilled
from Na/benzophenone, N-methyl pyrrolidone (NMP) and
DMSO (dimethyl sulfoxide) were distilled under N2 from
CaH2, DMF was distilled from P2O5 and Et2O was distilled
from LAH prior to use.
Figure 3. X-ray crystallographic structure of compound 15b: ORTEP view.
4.1.1. 3-(o-Bromophenyl)propan-1-al (4). To a solution of
selectively by appropriate choice of the electron with-
drawing substituents of the nucleophile. exo-Cyclizations
are observed when a sterically hindered nucleophile is
employed. endo-Cyclizations leading to octahydrophenan-
threne is the only reaction observed with a less sterically
demanding nucleophile. Notably, these cyclizations proceed
in a completely stereoselective trans manner. The reaction
is then stereospecific, the stereochemistry is defined by that
of the double bond in the initial substrate, the relative
configuration of the indane substrates are hereby controlled.
The biscyclization of acetylenic homologs could also be
performed leading exclusively to cyclopentylidenindane
structure, in that case the bulkiness of the nucleophile has no
effect on the course of the reaction.
Pd(OAc)2 (60 mg, 0.27 mmol), allylic alcohol (1.2 mL,
17.7 mmol), triethylbenzylammonium chloride (1.6 g,
7.1 mmol) and NaHCO3 (1.48 g, 17.7 mmol) in 50 mL of
DMF was added 1-bromo-2-iodobenzene (2.2 g, 7.9 mmol).
The black solution was heated at 50 8C for 24 h. The
mixture was quenched with saturated aqueous NH4Cl
solution (50 mL). The organic phase was extracted with
Et2O (3£100 mL), washed with brine (2£100 mL) and dried
over Na2SO4. The solvent was evaporated and the residue
purified by flash chromatography (PE/Et2O¼95:5) to give 4
as a yellow oil (1.15 g, 76%). 1H NMR (200 MHz, CDCl3) d
2.8 (2H, m), 3.1 (2H, m), 7.1 (1H, m), 7.25 (2H, m), 7.55
(1H, d, J¼7.9 Hz), 9.85 (1H, s). 13C NMR (50 MHz,
CDCl3) d 28.7, 43.6, 124.2, 127.6, 128.0, 130.5, 132.9,
139.7, 201.1. IR (neat): 3060, 2960, 2850, 2720, 1720, 1590,
1470, 1440, 1180, 1020, 750 cm21
.
4. Experimental
4.1. General
4.1.2. 5-(o-Bromophenyl)pent-1-en-3-ol (5). A solution of
vinylmagnesium bromide 1 M in THF (11.1 mL) was added
dropwise to a stirred solution of 4 (1.57 g, 7.37 mmol) in
THF (20 mL) maintained at 230 8C. The solution was
allowed to warm to room temperature. After stirring for 2 h,
All reactions were carried out under a nitrogen atmosphere
using standard syringe, cannula and septa techniques. All

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4013
the reaction was quenched with saturated aqueous NH4Cl
solution. The alcohol was extracted with Et2O (3£50 mL),
washed with brine (50 mL) and dried over Na2SO4. The
solvent was evaporated and the residue purified by flash
chromatography (PE/Et2O¼70:30) to give 5 as a yellow
(2.20 g, 14.7 mmol) was added. The mixture was refluxed
for 12 h and cooled to room temperature. Et2O (200 mL)
was added and the mixture was washed with a saturated
aqueous Na2S2O3 solution (2£100 mL), brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash chromatography using pure petroleum ether as
eluent to give the iodide 8 as a yellow oil (2.6 g, 92%).
1
liquid (1.71 g, 90%). H NMR (200 MHz, CDCl3) d 1.65
(1H, s), 1.75 (2H, m), 2.85 (2H, m), 4.15 (1H, m), 5.2 (2H,
m), 5.95 (1H, ddd, J¼17.2, 10.4, 6 Hz), 7.1 (1H, m), 7.25
(2H, m), 7.55 (1H, d, J¼7.7 Hz). 13C NMR (50 MHz,
CDCl3) d 32.2, 37.1, 72.6, 115.7, 124.6, 127.6, 127.8, 130.6,
133.0, 141.0, 141.3. IR (neat): 3400, 3060, 2920, 2860,
1640, 1570, 1470, 1020, 990, 920, 900 cm21. Anal. calcd
for C11H13OBr: C, 54.79; H, 5.43. Found: C, 55.20; H, 5.31.
A dispersion of 60% NaH in mineral oil (90.0 mg,
2.24 mmol) was suspended in a mixture of THF (5 mL)
and DMF (5 mL), and dimethylmalonate (282 mL,
2.47 mmol) was added dropwise. The resulting solution of
sodium malonate was added dropwise to a stirred solution of
the iodide derivative 8 (447 mg, 1.18 mmol) in THF
(7.5 mL) and DMF (7.5 mL) and the mixture was heated
overnight at 70 8C. The reaction was quenched with 5%
HCl. The malonate was extracted with Et2O (3£50 mL) and
the organic phase washed with brine (50 mL), dried and
concentrated in vacuo. The residue was purified by flash
chromatography (PE/Et2O¼80:20) to afford E1b as a
4.1.3. Ethyl (E)-7-(o-bromophenyl)hept-4-enoate (6). The
allylic alcohol 5 (1.71 g, 7.10 mmol) was refluxed with
freshly distilled triethyl orthoacetate (39 mL, 214 mmol)
and propionic acid (47 ml, 0.63 mmol) for 15 h. After
removal of triethyl orthoacetate under vacuum, the residual
oil was purified by flash chromatography (PE/Et2O¼70:30)
1
1
to give ester 6 as a yellow oil (1.76 g, 80%). H NMR
colorless oil (370 mg, 80%). H NMR (200 MHz, CDCl3)
(200 MHz, CDCl3) d 1.27 (3H, t, J¼7.2 Hz), 2.34 (6H, m),
2.78 (2H, m), 4.15 (2H, q, J¼7.2 Hz), 5.44 (1H, dt, J¼15.4,
6.3 Hz), 5.54 (1H, dt, J¼15.4, 6.3 Hz), 7.08 (1H, m), 7.25
(2H, m), 7.55 (1H, d, J¼7.7 Hz). 13C NMR (50 MHz,
CDCl3) d 14.3, 27.9, 32.6, 34.2, 36.1, 60.2, 124.4, 128.3,
127.5, 129.1, 130.2, 130.4, 132.7, 141.1, 173.1. IR (neat):
3060, 2980, 2860, 1740, 1570, 1470, 1440, 1370, 1180,
1020, 970, 750, 660 cm21. Anal. calcd for C15H19O2Br:
C, 57.81; H, 6.15; O, 10.28. Found: C, 57.96; H, 6.02; O,
10.41.
d 1.4 (2H, m), 1.95 (2H, m), 2.03 (2H, m), 2.3 (2H, m), 2.75
(2H, m), 3.36 (1H, t, J¼7 Hz), 3.75 (6H, s), 5.3–5.4 (2H, dt,
J¼15.1, 7 Hz), 7.19 (1H, m), 7.22 (2H, m), 7.53 (1H, d,
J¼7.5 Hz). 13C NMR (50 MHz, CDCl3) d 28, 32.2, 32.9,
36.4, 52.0, 52.6, 124.6, 127.4, 127.6, 129.9, 130.4, 130.6,
132.9, 141.0, 170.0. IR (neat): 3060, 2960, 2920, 2840, 1735
(broad), 1570, 1470, 1440, 1150, 1020, 970, 750 cm21
.
Anal. calcd for C18H23O4Br: C, 56.41; H, 6.05; O, 16.7.
Found: C, 56.62; H, 5.99; O, 16.9.
4.1.6. (E)-9-(2-Bromophenyl)-2-cyano-non-6-enoic acid
methyl ester (E1a). Prepared as above for compound E1b.
Colorless oil (42%). H NMR (200 MHz, CDCl3) d 1.31
(2H, m), 1.59 (2H, m), 1.88 (2H, m), 2.12 (2H, m), 2.79 (2H,
t, J¼22 Hz), 3.49 (1H, m), 3.82 (3H, s), 5.45 (2H, m), 7.09
(1H, m), 7.20 (2H, m), 7.51 (1H, d, J¼8.4 Hz). 13C NMR
(50 MHz, CDCl3) d 26.5, 29.2, 31.5, 32.7, 36.1, 38.8, 53.4,
116.4, 124.5, 127.3, 127.6, 129.5, 130.43, 130.45, 132.7,
141.1, 166.0. IR (neat): 3060, 2960, 2860, 2240, 1700, 1565,
1470, 1440, 1260, 1120, 1020, 970, 750, 650.
4.1.4. (E)-7-(o-Bromophenyl)hept-4-en-1-ol (7). A sol-
ution of ester 6 (1.88 g, 6.04 mmol) in dry Et2O (20 mL)
was added dropwise to a cold (0 8C) stirred suspension of
LAH (230 mg, 6.04 mmol) in dry Et2O (50 mL). The
mixture was stirred at room temperature for 1 h. Water
(0.230 mL), 1 N NaOH (0.230 mL) then 3 mL of water were
successively added until a precipitate appeared. The slurry
was filtered through a pad of celite and the filtrate was dried
over Na2SO4 and concentrated. The residual oil was purified
by flash chromatography using (PE/AcOEt¼90:10) to give
alcohol 7 as a yellow oil (1.24 g, 76%). 1H NMR (200 MHz,
CDCl3) d 1.38 (1H, s), 1.58 (2H, qn, J¼6.9 Hz), 2.06 (2H,
m), 2.3 (2H, m), 2.79 (2H, m), 3.61 (2H, t, J¼6.4 Hz), 5.44
(1H, dt, J¼15.4, 5.5 Hz), 5.53 (1H, dt, J¼15.4, 5.4 Hz), 7.08
(1H, m), 7.25 (2H, m), 7.55 (1H, d, J¼7.6 Hz). 13C NMR
(50 MHz, CDCl3) d 29.0, 32.4, 32.9, 36.4, 62.6, 124.6,
127.4, 127.7, 129.8, 130.60, 130.7, 132.9, 141.3. IR (neat):
3320, 3060, 2920, 2860, 1590, 1570, 1470, 1440, 1020, 970,
750, 660 cm21. Anal. calcd for C13H17OBr: C, 58.01; H,
6.37; O, 5.94. Found: C, 57.79; H, 6.26; O, 5.53.
1
4.1.7. (E)-2-[7-(2-Bromophenyl)-hept-4-enyl] malono-
nitrile (E1c). A dispersion of 60% NaH in mineral oil
(74.0 mg, 1.84 mmol) was suspended in THF (10 mL) and
cooled at 0 8C. Malononitrile (130 mg, 1.98 mmol) in THF
(10 mL) was added dropwise. The resulting solution of
sodium malononitrile was added at room temperature to a
solution of the iodide 8 (400 mg, 1.06 mmol) in THF
(10 mL). The resulting mixture was refluxed overnight in
THF. The reaction was quenched with a saturated aqueous
NH4Cl solution (20 mL). The dinitrile was extracted with
Et2O (3£50 mL) and the organic phase was washed with
brine (50 mL), dried and concentrated in vacuo. The residue
was purified by flash chromatography (PE/Et2O¼80:20) to
afford E1c as a colorless oil (172 mg, 50%). 1H NMR
(300 MHz, CDCl3) d 1.64 (2H, m), 1.89 (2H, m), 2.08 (2H,
m), 2.42 (2H, m), 2.8 (2H, m), 3.66 (1H, t, J¼7 Hz), 5.35
(1H, dt, J¼15.1, 7 Hz), 5.54 (1H, dt, J¼15.1, 7 Hz), 7–7.4
(3H, m), 7.52 (1H, d, J¼7.5 Hz). 13C (75 MHz, CDCl3) d
22.5, 26.1, 30.0, 31.0, 32.6, 35.9, 112.6, 124.4, 127.4, 127.6,
128.9, 130.5, 131.1, 132.8, 140.9. IR (neat): 3060, 2920,
2870, 2260, 1620, 1590, 1570, 1470, 1440, 1140, 1020, 970,
4.1.5. (E)-2-[7-(2-Bromophenyl)-hept-4-enyl] malonic
acid dimethyl ester (E1b). Methane sulfonyl chloride
(0.76 mL, 9.82 mmol) was added dropwise to a stirred
solution of alcohol 7 (2.00 g, 7.43 mmol) in a mixture of
CH2Cl2 (60 mL) and triethylamine (1.41 mL, 9.66 mmol).
After stirring for 2 h at 0 8C and 3 h at room temperature, the
reaction mixture was diluted with diethyl ether (150 mL)
and the mixture was washed with a saturated aqueous
NH4Cl solution (70 mL), dried and concentrated in vacuo.
The residue was dissolved in acetone and sodium iodide

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4014
750 cm21. Anal. calcd for C16H17N2Br: C, 60.58; H, 5.40.
Found: C, 60.80; H, 5.51.
mixture was stirred at 50 8C for 65 h. The solution was
directly purified by flash chromatography (PE/Et2O¼90:10)
to give trans-2c as a pure white solid (90 mg, 52%). IR
(KBr): 3060, 2940, 2215, 1600. 1H NMR (300 MHz, C6D6)
d 0.6 (1H, tdt, J¼12.5, 12.5, 3.9 Hz), 1.1–1.4 (4H, m), 1.50
(1H, dt, J¼4.3, 12 Hz), 1.70 (1H, dt, J¼12.7, 3.4 Hz), 1.8
(1H, dd, J¼13.3, 3 Hz), 1.95 (1H, ddt, J¼12.6, 5.4 Hz), 2.35
(1H, m), 2.35 (2H, m), 6.8–7.2 (4H, m). 13C NMR
(75 MHz, CDCl3) d 21.9, 26.3, 28.9, 29.3, 34.8, 38.6,
39.3, 45.7, 116.0, 126.3, 126.6, 126.8, 129.3, 135.6, 137.2.
Anal. calcd for C16H16N2: C, 81.35; H, 6.82. Found: C,
81.14; H, 6.72. Mp 174–176 8C.
4.2. General procedure for the preformation of the
palladium (0) complex and formation of 2-indan-1-
ylcyclopentane-1,1-dicarboxylic acid dimethyl ester
(anti-3b)
The Pd (0) complex was preformed using the same
experimental procedure for all cyclizations. Under N2, a
mixture of 5 mol% of Pd(OAc)2, 10 mol% of dppe (1,2-
bis(diphenylphosphino)ethane) and 10 mol% of 1-heptene
in NMP (N-methyl pyrrolidone) was stirred and heated with
a hairdrier until the mixture turned brick-red. On the one
hand, a solution of tBuOK (49 mg, 0.43 mmol) and 18-
crown-6 (21 mg, 0.08 mmol) in NMP (1 mL) was added to a
solution of malonate E1b (150 mg, 0.39 mmol) in NMP
(2 mL). The mixture was stirred at room temperature for
30 min. On the other hand, the palladium (0) complex was
preformed in NMP (2 mL) by reaction of 1-heptene
(0.56 mL, 0.04 mmol) with Pd(OAc)2 (4.50 mg,
0.02 mmol) and dppe (15.9 mg, 0.04 mmol). The addition
of the brick-red Pd(0) solution was made via a cannula to the
malonate solution prepared above. The mixture was stirred
at 50 8C for 3 h. The solution was directly purified by flash
chromatography (PE/Et2O¼80:20) to afford anti-3b as a
pure white solid (65 mg, 55%). 1H NMR (300 MHz, CDCl3)
d 1.45 (1H, ddd, J¼3.6, 8.7, 13.5 Hz), 1.65 (1H, ddd, J¼7.9,
11.2, 14.2 Hz), 1.85 (2H, m), 2.10 (3H, m), 2.56 (1H, dt,
J¼8.1, 13.6 Hz), 2.75 (2H, m), 3.0 (1H, dt, J¼2.8, 10 Hz),
3.10 (1H, ddd, J¼7.1, 9.7, 13.8 Hz), 3.75 (6H, s), 7.10–7,53
(4H, m). 13C NMR (75 MHz, CDCl3) d 23.5, 30.9, 31.6,
31.9, 37.3, 47.6, 49.9, 52.2, 52.6, 63.0, 124.6, 125.5, 125.6,
126.6, 144.7, 146.6, 172.3, 174.0. IR (KBr): 3060, 2940,
2840, 1740. Anal. calcd for C18H22O4: C, 71.50; H, 7.33.
Found: C, 71.29; H, 7.68. Mp 50–52 8C.
4.2.3. X-ray crystal structure analysis. Crystal data for
trans-2c at 295 K collected on a Nonius CAD 4. C16H16N2,
M¼236.31, monoclinic, C2/c, a¼26.332(4), b¼7.4772(7),
˚
c¼17.345(3) A, a¼90, b¼130.648(12), g¼908, V¼
3
˚
˚
2591.2(6) A ,
Z¼8,
l(Cu Ka)¼1.54056 A,
Dc¼
1.212 g cm23, 2585 reflections, 211 parameters, R¼0.0615
and Rw¼0.1800 for 2264 reflections with I.2s(I). CCDC
registration number 221276.
4.2.4. (Z)-2-[7-(2-Bromophenyl)-hept-4-enyl] malonic
acid dimethyl ester (Z1b). 8.16 g (18.8 mmol) of
phosphonium salt of 1-bromo-4-chlorobutane and 3.83 g
(19.2 mmol) of potassium hexamethyldisilazane (KHMDS)
were placed in a round bottomed flask flushed with N2. At
0 8C, 77 mL of dry THF were added dropwise, the mixture
turning to orange solution. After 15 min at 0 8C, aldehyde 4
(2.0 g, 9.4 mmol) in THF (17 mL) was added dropwise to
the ylide solution and the resulting betaine-ylide solution
was stirred at 0 8C for 3 h. The solvent was partially
removed in vacuo and 20 mL of pentane were added in
order to precipitate triphenylphosphine oxide. Filtration
through a pad of silica gel and removal of solvent under
reduced pressure gave a crude oil. Chromatography on silica
gel using PE as eluent gave the compound 9 (1.76 g, 65%).
1H NMR (300 MHz, CDCl3) d 1.73 (2H, qn, J¼6.7 Hz),
2.14 (2H, m), 2.40 (2H, m); 2.70 (2H, t, J¼7.5 Hz); 3.47
(2H, t, J¼7 Hz), 5.38 (1H, dt, J¼11, 7 Hz), 5.49 (1H, dt,
J¼11, 7 Hz), 7.1 (1H, m), 7.2 (2H, m), 7.55 (1H, d,
J¼7 Hz). 13C NMR (50 MHz, CDCl3) d 24.4, 27.5, 32.4,
36.2, 44.4, 124.4, 127.2, 127.6, 128.9, 129.8, 130.5, 132.8,
141.0. IR (neat): 3050, 2960, 2870, 1570, 1470, 1440, 1200,
4.2.1. trans-2-Cyano-1,2,3,4,4a,9,10,10a-octahydro-
phenanthrene-2-carboxylic acid methyl ester (trans-2a)
and 1-cyano-2-indan-1-yl-cyclopentanecarboxylic acid
methyl ester (anti-3a). Same experimental procedure as
for E1b. The mixture was stirred at 50 8C for 24 h. The
solution was directly purified by flash chromatography (PE/
Et2O¼80:20) to give trans-2a and anti-3a (combined yield:
70%).
1120, 1050, 1025, 920, 750, 700 cm21
.
trans-2a: 1H NMR (400 MHz, CDCl3) d 1.15–1.30 (1H, m),
1.65–1.82 (2H, m), 1.83–1.98 (4H, m), 2.12 (1H, ddd,
J¼12.1, 11.3, 3.9 Hz), 2.5 (1H, m), 2.81 (3H, m), 3.8 (3H,
s), 7–7.25 (4H, m). 13C NMR (75 MHz, CDCl3) d 22.6,
26.0, 29.3, 30.1, 34.4, 38.8, 44.5, 52.1, 53.5, 117.8, 125.7,
126.1, 126.2, 129.0, 135.9, 138.2, 170.0.
Following the same experimental procedure as for E1b,
using iodide 10 as intermediate, the residue was purified by
flash chromatography (PE/Et2O¼80:20) to afford Z1b as an
oil (292 mg, 74%). 1H NMR (300 MHz, CDCl3) d 1.4 ppm
(2H, m), 1.87 (2H, q, J¼7.7 Hz), 2.00 (2H, q, J¼7.1 Hz);
2.30 (2H, q, J¼7.7 Hz), 2.76 (2H, t, J¼7.7 Hz), 3.33 (1H, t,
J¼7.7 Hz), 3.75 (6H, s); 5.3–5.6 (2H, dt, J¼10.7, 7 Hz),
7.05 (1H, m), 7.25 (2H, m), 7.5 (1H, d, J¼8 Hz). 13C NMR
(50 MHz, CDCl3) d 26.7, 27.3, 27.6, 28.2, 36.2, 51.2, 52.4,
124.4, 127.3, 127.6, 129.0, 129.9, 130.6, 132.7, 141.0, 169.8.
IR (neat): 3010, 2960, 2930, 2860, 1750 (broad), 1570,
1470, 1440, 1350, 1150, 1020, 750, 660 cm21. Anal. calcd
for C18H23O4Br: C, 56.41; H, 6.05. Found: C, 56.81; H, 6.25.
anti-3a: 1H NMR (400 MHz, CDCl3) d 1.72–2.10 (3H, m),
2.17–2.38 (4H, m), 2.50 (1H, m), 2.70 (1H, m), 2.79–3.01
(2H, m), 3.4 (1H, ddd, J¼11.5, 8.3, 7.1 Hz), 3.90 (3H, s),
7.14–7.35 (4H, m). 13C NMR (75 MHz, CDCl3) d 23.5,
31.0, 31.1, 31.3, 39.7, 48.3, 52.6, 53.0, 53.6, 118.8, 124.7,
124.8, 125.9, 126.9, 144.1, 145.3, 171.1.
4.2.2. trans-3,4,4a,9,10,10a-Hexahydro-2H-phenan-
threne-1,1-dicarbonitrile (trans-2c). Same experimental
procedure as for E1b. Scale: 234 mg, 0.74 mmol of E1c.The
4.2.5. (Z)-9-(2-Bromophenyl)-2-cyano-non-6-enoic acid
methyl ester (Z1a). Same experimental procedure as for
E1b. Colorless oil (35%). H NMR (200 MHz, CDCl3) d
1

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4015
1.40–1.60 (2H, m), 1.80–1.92 (2H, m), 1.98–2.08 (2H, m),
4.3. Alkyne series
2.29–2.40 (2H, m), 2.76 (2H, t, J¼7 Hz), 3.46 (1H, t,
J¼7 Hz), 3.81 (3H, s), 5.28–5.55 (2H, m), 7.0–7.09 (1H,
m), 7.19–7.25 (2H, m), 7.51 (1H, d, J¼7.6 Hz). 13C NMR
(50 MHz, CDCl3) d 26.2, 26.6, 27.6, 29.3, 36.1, 37.3, 53.4,
116.4, 124.4, 127.3, 127.6, 129.2, 129.5, 130.7, 132.7,
140.9, 166.6. IR (neat): 3060, 3010, 2940, 2870, 2250, 1760,
4.3.1. 4-(o-Bromophenyl)-but-1-yne (11). In a round
bottom flask flushed with N2 were placed magnesium
turnings (1.42 g, 58.3 mmol) and HgCl2 (48 mg,
0.18 mmol) in diethyl ether (10 mL). At room temperature,
few drops of pure propargyl bromide were added. After
some minutes an exothermic reaction started and the
mixture was cooled to 0 8C. When the exothermic reaction
has subsided, the remainder of the propargyl bromide
(3.6 mL, 48 mmol) in diethyl ether (20 mL) was added
dropwise over a period of 1 h, while the temperature was
maintained at 0 8C. After completion of the addition, the
mixture was stirred for 1 h at 0 8C. Then the Grignard
solution was allowed to warm to room temperature and was
added via a cannula to a solution of 2-bromobenzyl bromide
(10 g, 40 mmol) in THF (50 mL). After stirring at room
temperature for 3 h the mixture was quenched with water
(100 mL) and extracted with diethyl ether (3£100 mL). The
organic layer was washed with brine (100 mL), dried and
concentrated. To eliminate the excess of 2-bromobenzyl
bromide the crude oil was dissolved in DMSO and sodium
cyanide (6 g) was added (3 g/100 mL DMSO). After stirring
for 12 h at room temperature the formation of polar
2-bromobenzyl cyanide was occurred. The mixture was
quenched with water (200 mL), extracted with Et2O
(2£150 mL) and washed with brine (150 mL). The organic
layer was dried, concentrated and purified by chromatog-
raphy (PE/Et2O¼90:10) to afford 11 as a colorless oil
1570, 1470, 1260, 1210, 1020, 970 cm21
.
4.2.6. (Z)-2-[7-(2-Bromophenyl)-hept-4-enyl] malono-
nitrile (Z1c). Same experimental procedure as for E1c.
Scale: 500 mg, 1.32 mmol of iodide 10. The residue was
purified by flash chromatography (PE/Et2O¼70:30) to
1
afford Z1c as an oil (180 mg, 31%). H NMR (300 MHz,
CDCl3) d 1.5 (2H, m), 1.8 (2H, m), 2.2 (2H, m), 2.35 (2H,
m), 2.8 (2H, m), 3.66 (1H, t, J¼7 Hz), 5.36 (1H, dt, J¼10.7,
7 Hz), 5.52 (1H, dt, J¼10.7, 7 Hz), 7.1 (1H, m), 7.2 (2H, m),
7.5 (1H, d, J¼7.5 Hz). 13C NMR (75 MHz, CDCl3) d 22.6,
25.8, 26.4, 27.7, 30.2, 36.1, 112.6, 125, 127.5, 127.9, 128.6,
130.4, 130.9, 132.4, 141. IR (neat): 3060, 3010, 2980, 2925,
2860, 2260, 1570, 1470, 1440, 1030, 970, 750, 660 cm21
.
Anal. calcd for C16H17N2Br: C, 60.58; H, 5.40. Found: C,
60.81; H, 5.53.
4.2.7. 2-Indan-1-ylcyclopentane-1,1-dicarboxylic acid
dimethylester (syn-3b). Same experimental procedure as
for E1b. Scale: 120 mg, 0.3 mmol of Z1b. The mixture was
stirred at 50 8C for 15 h. The solution was directly purified
by flash chromatography (PE/Et2O¼80:20) to give (82 mg,
90%) of syn-3b as a yellow oil. 1H NMR (300 MHz, CDCl3)
d 1.5 (3H, m), 1.75 (2H, m), 2.0 (2H, m), 2.5 (1H, ddd,
J¼7.1, 8.5, 13.6 Hz), 2.85 (2H, m), 3.2 (1H, dt, J¼2.9,
7.2 Hz), 3.6 (1H, dt, J¼2.9, 10 Hz), 3.75 (6H, s), 7.1–7.34
(4H, m). 13C NMR (75 MHz, CDCl3) d 22.9, 26.4, 29.9,
32.2, 34.8, 44.7, 50.1, 52.6, 62.9, 123.9, 124.3, 126.4, 126.6,
143.7, 146.9, 173.0. IR (neat): 3060, 2940, 2840, 1740.
Anal. calcd for C18H22O4: C, 71.50; H, 7.33. Found: C,
71.45; H, 7.54.
1
(6.23 g, 75%). H NMR (300 MHz, CDCl3) d 2.0 (1H, t,
J¼2.5 Hz), 2.54 (2H, td, J¼2.5, 7.5 Hz), 3.0 (2H, t,
J¼7.5 Hz); 7.1 (1H, m), 7.2 (2H, m), 7.56 (1H, d,
J¼7 Hz). 13C NMR (75 MHz, CDCl3) d 18.8, 35.1, 69.1,
83.3, 124.0, 127.4, 128.2, 130.5, 130.8, 132.8.
4.3.2. 2-[7-(2-Bromophenyl)-hept-4-ynyl] malonic acid
dimethyl ester (14a). At 220 8C, nBuLi (2.5 M in hexane)
(2.11 mL, 5.28 mmol) was added dropwise to a solution of
diisopropylamine (0.88 mL, 6.22 mmol) in THF (2 mL).
The LDA solution was stirred for 1 h at 220 8C and was
cooled to 278 8C. A solution of 11 (1.0 g, 4.8 mmol) in
THF (2 mL) was added via a canula to the LDA solution.
The mixture was stirred for 1 h at 278 8C. Finally, 1-bromo-
3-chloropropane (0.71 mL, 7.2 mmol) was added via a
syringe. The solution was allowed to warm at RT and was
refluxed overnight. The mixture was cooled to RT,
quenched with saturated aqueous NH4Cl solution, extracted
with Et2O (3£50 mL). The organic layer was washed with
brine (50 mL), dried and concentrated. The excess of
1-bromo-3-chloropropane was eliminated by distillation
under atmospheric pressure. The starting material 11 was
trapped in Et2O (12 h, RT) by an aqueous solution of silver
nitrate (14% in weight). The formation of water insoluble
silver acetylide occurred. The mixture was diluted with
Et2O (20 mL), washed with water (10 mL) and brine
(10 mL). The organic layer was dried, concentrated and
purified by chromatography using PE as eluent to afford 12
as an yellow oil (1.48 g, 60%). 1H NMR (300 MHz, CDCl3)
d 1.9 ppm (2H, t, J¼7.3 Hz), 2.33 (2H, m), 2.48 (2H, m);
2.93 (2H, t, J¼7.4 Hz), 3.58 (2H, t, J¼6.6 Hz), 7.10 (1H,
m), 7.25 (2H, m), 7.5 (1H, d, J¼7.9 Hz). 13C NMR
(50 MHz, CDCl3) d 19.1, 19.6, 32.2, 35.6, 44.4, 71.0,
80.0, 124.0, 127.2, 128.1, 130.7, 132.8, 141.0. IR (neat):
4.2.8. cis-3,4,4a,9,10,10a-Hexahydro-2H-phenanthrene-
1,1-dicarbonitrile (cis-2c). For dicarbonitrile compound,
the experimental procedure was identical as previously.
Scale: 210 mg, 0.66 mmol of Z1c. The mixture was stirred
at 50 8C for 48 h. The solution was directly purified by flash
chromatography (PE/Et2O¼90:10) to give cis-2c in 58%
1
yield (90 mg) as a pure white solid. H NMR (300 MHz,
C6D6) d 0.7–1.5 (7H, M), 1.6 (1H, ddt, J¼13, 3, 1.5 Hz), 1.8
(1H, dt, J¼13.2, 3.7 Hz), 2.25 (1H, ddd, J¼17, 12, 6 Hz),
2.45 (1H, dd, J¼17, 6 Hz), 2.8 (1H, dt, J¼12.6, 3.7 Hz), 7.2
(4H, m). 13C NMR (75 MHz, CDCl3): d 19.5, 21.8, 28.0,
29.0, 29.5, 36.8, 37.0, 40.0, 116.0, 126.3, 126.7, 129.0,
129.2, 134.4, 139.0. IR (KBr): 3060, 2940, 2215. Anal.
calcd for C16H16N2: C, 81.30; H, 6.82. Found: C, 81.03; H,
6.80. Mp 113–115 8C.
4.2.9. X-ray crystal structure analysis. Crystal data for
cis-2c at 293 K collected on a Nonius CAD 4. C16H16N2,
M¼236.32, triclinic, P21, a¼9.218(1), b¼9.596(1), c¼
˚
16.064(2) A, a¼75.50(1), b¼74.89(1), g¼75.01(1)8, V¼
3
23
˚
˚
1299.3(3) A , Z¼4, l(CuKa)¼1.54056 A, Dc¼1.209 g cm
,
5202 reflections, 421 parameters, R¼0.072 and Rw¼0.127
for 4496 reflections with I.3s(I). CCDC registration
number 221277.

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D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4016
3060, 2960, 2920, 2860, 1570, 1470, 1440, 1290, 1120,
1020, 750 cm21
was preformed using the same procedure as the olefinic
compound (concentration 0.05 M in DMSO). tBuOK
(41 mg, 0.36 mmol) and 18-C-6 crown ether in DMSO
(0.33 mL) were added to a solution of 14a (125 mg,
0.33 mmol) in DMSO (0.66 mL). The sodium enolate
solution was stirred for 30 min at RT. The palladium zero
solution was added via a cannula to the sodium enolate
solution and the mixture was stirred at 90 8C for 2 h. The
mixture was cooled to RT, quenched with water, extracted
with Et2O (2£10 mL) and the organic layer was washed
with brine (10 mL), dried, concentrated and purified by
chromatography (PE/Et2O¼90:10) to afford 15a as an
.
12 (433 mg, 1.52 mmol) and sodium iodide (0.5 g,
3.3 mmol) were dissolved in acetone (10 mL) The solution
was refluxed overnight and cooled to room temperature. The
mixture was diluted in Et2O (50 mL) and washed with
saturated aqueous Na2S2O3 solution (10 mL). The organic
layer was dried, concentrated and purified by chromato-
graphy using PE to afford 13 as a pale yellow oil (507 mg,
1
88%). H NMR (300 MHz, CDCl3) d 1.93 (2H, m), 2.27
(2H, m), 2.48 (2H, m), 2.93 (2H, t, J¼7.4 Hz), 3.23 (2H, t,
J¼6.6 Hz), 7.1 (1H, m), 7.25 (2H, m), 7.52 (1H, d,
J¼7.9 Hz). 13C NMR (50 MHz, CDCl3) d 6.3, 19.1, 19.7,
32.3, 35.5, 70, 80, 124, 127.3, 128, 130.7, 132.7, 141. IR
(neat): 3060, 2960, 2920, 2860, 1570, 1470, 1440, 1220,
1
yellow oil (57 mg, 58%). H NMR (300 MHz, CDCl3): d
1.87 (2H, t, J¼7.2 Hz), 2.47 (2H, t, J¼7.2 Hz), 2.72 (2H,
m), 2.82 (2H, t, J¼6.3 Hz), 2.97 (2H, t, J¼6.3 Hz), 3.70
(6H, s), 7.22 (3H, m), 7.53 (1H, d, J¼6.3 Hz). 13C NMR
(75 MHz, CDCl3): d 25.3, 30.68, 30.73, 33.2, 38.8, 52.7,
60.7, 124.9, 125.1, 126.2, 127.4, 132.7, 140.2, 142.3, 147.6,
171.9. MS m/z: 300.05 (16), 236 (12), 210.15 (16), 209.05
(100), 208.05 (54), 207.05 (12), 181.15 (14), 165.05 (13). IR
(neat): 3060, 2940, 1750, 1430, 1250.
1020, 750, cm21
.
At room temperature, NaH (90.5 mg, 3.77 mmol) washed in
pentane was suspended in THF (25 mL) and dimethyl-
malonate (0.48 mL, 4.17 mmol) was added dropwise. The
sodium enolate solution was stirred for 30 min at RT and
was added dropwise to a solution of 13 (750 mg,
1.99 mmol) in DMF (15 mL). The resulting mixture was
refluxed overnight and cooled to RT. The mixture was
quenched with saturated aqueous NH4Cl solution, extracted
with Et2O (3£50 mL) and washed with brine (50 mL). The
organic layer was dried, concentrated and purified by
chromatography (PE/Et2O¼90:10) to afford 14a as a
4.3.5. 1-Cyano-2-indan-1-ylidene cyclopentane-
carboxylic acid methyl ester (15b). For dicarbonitrile
compound 14b (93 mg, 0.32 mmol) the experimental
procedure was identical as previously, the mixture was
stirred at 90 8C for 2 h and cooled to RT. The mixture
was filtered through silica gel (PE/Et2O¼90:10) and was
concentrated to afford 15b as a transparent crystalline solid
(34 mg, 50%). 1H NMR (300 MHz, CDCl3): d 2.12 (2H, q,
J¼6.9 Hz), 2.64 (2H, t, J¼7 Hz), 2.89 (2H, t, J¼7 Hz), 3.15
(4H, s), 7.1–7.4 (3H, m), 7.5 (1H, d, J¼7 Hz). 13C NMR
(75 MHz, CDCl3): d 25.6, 30.6, 30.7, 31.9, 37.8, 41.0,
115.0, 124.6, 125.3, 125.6, 126.7, 129.2, 140.1, 144.5,
148.8. MS m/z: 234 (74), 206 (35), 205 (20), 178 (10), 156
(100), 155 (27), 116 (21), 115 (32). IR (neat): 3080, 2940,
2860, 2220. Mp 137–139 8C.
1
colorless oil (593 mg, 80%). H NMR (200 MHz, CDCl3)
d 1.48 (2H, m), 1.98 (2H, td, J¼7.5 Hz), 2.19 (2H, tt, J¼2.2,
7.5 Hz), 2.48 (2H, tt, J¼2.2, 7.5 Hz), 2.91 (2H, t, J¼7.5 Hz),
3.38 (1H, t, J¼7.5 Hz), 3.75 (6H, s), 7.1–7.3 (3H, m), 7.51
(1H, d, J¼8.1 Hz). 13C NMR (50 MHz, CDCl3) d 18.5, 19.2,
26.6, 28.0, 35.7, 51.3, 52.5, 79.7, 80.1, 124.4, 127.3, 128.0,
130.8, 132.7, 140.0, 169.7. IR (neat): 3000, 2950, 1750 (br),
1440, 1390, 1200, 1150, 1030, 850, 755 cm21. Anal. calcd for
C18H21O4Br: C, 56.70; H, 5.56. Found: C, 56.54; H, 5.65.
4.3.6. X-ray crystal structure analysis. Crystal data for
15b at 295 K collected on a Nonius Kappa CCD. C16H14N2,
M¼234.3, triclinic, P21, a¼7.546(2), b¼10.267(2),
4.3.3. 2-[7-(2-Bromophenyl)-hept-4-ynyl] malononitrile
(14b). Under N2 at 0 8C malononitrile (131 mg, 1.98 mmol)
in THF (1 mL) was added dropwise to a solution of NaH
washed in pentane (44 mg, 1.84 mmol) in THF (3.5 mL).
After stirring at RT for 30 min, the sodium enolate solution
was added dropwise to a solution of 13 (500 mg,
1.32 mmol) in THF (1 mL). The resulting mixture was
refluxed overnight and cooled to RT. The solution was
quenched with saturated aqueous NH4Cl solution, extracted
with Et2O (3£50 mL) and washed with brine (50 mL). The
organic layer was dried, concentrated and purified by
chromatography (PE/Et2O¼85:15) to afford 14b as an
˚
c¼17.602(4) A, a¼100.67(3), b¼96.03(3), g¼108.85(3)8,
3
˚
˚
V¼1248.3(4) A , Z¼4,
l
(Mo Ka)¼0.71073 A, Dc¼
1.247 g cm23, 5664 reflections, 325 parameters, R¼0.0502
and Rw¼0.1072 for 1776 reflections with I.4s(I). CCDC
registration number 221278.
4.4. X-ray diffraction studies
Crystallographic data have been deposited with the Cam-
bridge Crystallographic Data Centre (see registration
numbers in experimental). Copies of the data can be
obtained on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).
1
yellow oil (186 mg, 45%). H NMR (200 MHz, CDCl3) d
1.78 (2H, m), 2.07 (2H, m), 2.28 (2H, m), 2.51 (2H, m), 2.94
(2H, t, J¼7.3 Hz), 3.74 (1H, t, J¼7 Hz), 7.05 (1H, m),
7.2 (2H,m), 7.51 (1H, d, J¼8.1 Hz). 13C NMR
(50 MHz,CDCl3): d 17.7, 19.1, 22.3, 25.4. 29.9, 35.4,
78.7, 81.2, 112.5, 124.5, 127.4, 128.2, 130.7, 132.1, 139.8.
IR (neat): 3060, 2950, 2860, 2260, 1440, 1030, 750 cm21
.
Acknowledgements
Anal. calcd for C16H15N2Br: C, 60.96; H, 4.80. Found: C,
61.37; H, 5.1.
`
D. Bruyere wishes to thank the Ministere de l’Education
Nationale, de la Recherche et de la Technologie for a
`
´
fellowship. The authors thank Prof. Rene Faure for X-ray
diffraction analysis.
4.3.4. 2-Indan-1-ylidenecyclopentane-1,1-dicarboxylic
acid dimethylester (15a). The palladium zero complex

`
D. Bruyere et al. / Tetrahedron 60 (2004) 4007–4017
4017
Monteiro, N.; Bouyssi, D.; Balme, G. J. Organomet. Chem.
2003, 687(2), 466.
References and notes
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8. The palladium diphenylphosphinoethane was preformed
by heating Pd(OAc)2 (0.05 mol equiv.) and dppe (0.05 mol
equiv.) in the presence of 1-heptene (0.1 equiv.) in 1 mL of
solvent until homogeneous dark red solution was obtained.
9. J couplings were best measured on the 1D after assignment
from the 2D spectra.
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¨
(h) Brase, S.; de Meijere, A. In Metal-catalyzed cross-
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¨
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